WO2018158763A1 - Composition parodontale et procédé d'utilisation - Google Patents

Composition parodontale et procédé d'utilisation Download PDF

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Publication number
WO2018158763A1
WO2018158763A1 PCT/IL2018/050217 IL2018050217W WO2018158763A1 WO 2018158763 A1 WO2018158763 A1 WO 2018158763A1 IL 2018050217 W IL2018050217 W IL 2018050217W WO 2018158763 A1 WO2018158763 A1 WO 2018158763A1
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Prior art keywords
composition
present
agent
periodontal
polymer
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PCT/IL2018/050217
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English (en)
Inventor
Keren MEVORAT KAPLAN
Dadi Segal
Danny ROSENBAUM
Igal LIAPIS
Igor Makarovsky
Meir Stern
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Prudentix Ltd.
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Application filed by Prudentix Ltd. filed Critical Prudentix Ltd.
Publication of WO2018158763A1 publication Critical patent/WO2018158763A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0063—Periodont

Definitions

  • the present invention relates to an oral delivery composition, more particularly a solid dosage form, for delivering a therapeutic agent, e.g., an antibacterial agent, to a soft tissue in the oral cavity such as a periodontal pocket so as to treat an oral cavity related disease such as periodontal disease; and to a method of use.
  • a therapeutic agent e.g., an antibacterial agent
  • Periodontal diseases are common ailment which affect high proportion of the population especially at advanced age. Gingivitis, often caused by inadequate oral hygiene, is the mildest form of a periodontal disease that causes the gingiva (or gums) to become red, swollen, and bleed easily. While gingivitis can be reversible with professional treatment and good oral home care, untreated gingivitis can advance to periodontitis. With time, plaque can spread and grow below the gum line. Toxins produced by the bacteria in plaque irritate the gums, and stimulate a chronic inflammatory response following which the tissues and bone supporting the teeth are broken down and destroyed. Consequently, gums separate from the teeth, forming pockets (spaces between the teeth and gums) that become infected. As the disease progresses, those pockets deepen and more gum tissue and bone are destroyed. Often, this destructive process has very mild symptoms. Eventually, teeth may become loose and might have to be removed.
  • periodontal diseases are more difficult to treat, inter alia, due to the markedly different environments of the oral and periodontal cavities.
  • the oral cavity is essentially an aerobic environment constantly perfused by saliva
  • the periodontal microenvironment is more anaerobic and perfused by a plasma filtrate known as the "crevicular fluid" .
  • the growth of microorganisms within the periodontal microenvironment may cause periodontal disease, and as the periodontal disease becomes more established, said microenvironment becomes more anaerobic and the flow of crevicular fluid increases.
  • antimicrobial agents introduced to the oral cavity are generally ineffective.
  • antibacterial agents such as chlorhexidine and quaternary ammonium salts, in the form of mouth rinses, have proved to be successful in preventing periodontal disease (Loe et ah, 1970).
  • these agents when administered in the form of mouth rinses, these agents have no effect on the subgingival flora as they do not penetrate into the pockets resulting from the disease.
  • oral usage of chlorhexidine even for short periods of time, may have side effects such as tooth discoloration.
  • nonbiodegradable devices are capable of dispensing an appropriate ingredient for a time span of a week or more, they are inappropriate for widespread use as they are difficult to apply and in certain cases must be dislodged in an operative procedure carried out by a dentist.
  • Degradable polymers and copolymers that have been substantially investigated as potential implant compositions include poly(lactic acid) (Kulkarni et ah, 1966), poly(glygolic acid) (US 2,676,945), and poly(lactic acid)poly(glycolic acid) copolymer (US 3,397,033); and the properties and uses of such polymers and/or copolymers have been disclosed (FR 2,059,690 and FR 2,059,691; JP 72-43,220; US 3,642,003).
  • the biodegradation of poly(lactic acid) and poly(glycolic acid) may require three to five months (FR 1,478,694; Darkik, 1971), and it may thus not be advisable to employ implants composed of such polymers where a more rapid biodegradation is desired.
  • the present invention provides an oral delivery composition, said composition being in a solid dosage form comprising: (i) a matrix comprising a water insoluble biodegradable or bioerodible pharmaceutically acceptable polymer, low molecular weight hyaluronic acid or a salt thereof, and a cross-linking agent cross linking said polymer and said hyaluronic acid or salt thereof; (ii) a plasticizer; and (iii) a therapeutic agent, more specifically an antibacterial agent, wherein upon contact with a fluid, e.g., an aqueous fluid, said composition adsorbs said fluid and consequently swells, and then degrades and releases said therapeutic agent in a sustained release manner.
  • a fluid e.g., an aqueous fluid
  • said solid dosage form is an essentially two-dimensional (or practically flat three-dimensional) solid implant adapted for implantation in a periodontal pocket, e.g., a solid implant that is from about 3 to about 10 mm in length, from about 1 to about 5 mm in width, and from about 0.01 to 0.5 mm in thickness.
  • the present invention relates to a method for treatment of periodontal disease in a subject in need thereof comprising the step of implantation of an oral delivery composition as defined above (e.g., such a composition comprising an antibacterial agent), i.e., a solid dosage form, that is an essentially two-dimensional (or practically flat three-dimensional) solid implant adapted for implantation in a periodontal pocket of said subject, to thereby release said therapeutic agent in said periodontal pocket in a sustained release manner.
  • an oral delivery composition as defined above (e.g., such a composition comprising an antibacterial agent), i.e., a solid dosage form, that is an essentially two-dimensional (or practically flat three-dimensional) solid implant adapted for implantation in a periodontal pocket of said subject, to thereby release said therapeutic agent in said periodontal pocket in a sustained release manner.
  • the present invention relates to an oral delivery composition as defined above (e.g., such a composition comprising an antibacterial agent), i.e., a solid dosage form, that is an essentially two-dimensional (or practically flat three-dimensional) solid implant adapted for implantation in a periodontal pocket, for use in the treatment of periodntal disease.
  • a composition comprising an antibacterial agent i.e., a solid dosage form, that is an essentially two-dimensional (or practically flat three-dimensional) solid implant adapted for implantation in a periodontal pocket, for use in the treatment of periodntal disease.
  • Fig. 1 shows the swelling of the commercial product (Periochip) vs. that of the Periodontal film shown in Study 1 , indicting that the initial swelling of the Periochip is faster, reaching more than 400 percent; however, it falls down within half an hour, whereas the swelling of the Periodontal film is around 240 percent and it stays constant.
  • Fig. 2 shows the changes (%) in the X dimension of the Periodontal film shown in Study 1 vs. Periochip in water, as measured at room temperature after incubation at 37°C, at different time points over 60 minutes in total. Each experiment was conducted in duplicates.
  • Fig. 3 shows the changes (%) in the Y dimension of the Periodontal film shown in Study 1 vs. Periochip in water, as measured at room temperature after incubation at 37°C, at different time points over 60 minutes in total. Each experiment was conducted in duplicates.
  • Fig. 4 shows the changes (%) in the Z dimension of the Periodontal film shown in Study 1 vs. Periochip in water, as measured at room temperature after incubation at 37°C, at different time points over 60 minutes in total. Each experiment was conducted in duplicates.
  • Fig. 5 schematically illustrates the swelling of the Periodontal film shown in Study 1 (middle and left side) vs. that of PeriochipTM (right side), showing that Periodontal film swells in the z direction (top-bottom direction) substantially more than in the planar x and y (horizontal) directions, as opposed to the commercial product (Periochip) wherein swelling is substantially higher in the x-y horizontal directions.
  • Left scheme represents a slice cut from the Periodontal film prepared (an essentially two-dimensional solid implant).
  • Fig. 6 schematically depicts a Periodontal film inside a periodontal pocket.
  • Figs. 7A-7B show AFM images (top tiew) of the composite film shown in Study 1 (7A, 400-700 nm features) and of the commercial product, Periochip (7B, 200-400 nm features). Both images cover area of 20x20 ⁇ .
  • Figs. 8A-8B are three-dimensional images showing deeper and wider clefts in the composite film shown in Study 1 (8A) compared to Periochip (8B). Both images cover area of 20x20 ⁇ . The larger features (400-700 nm) of the surface shown in the image of 9A are probably due to the different surface composite (hyaluronan enriched) of the periodontal film. The imaging was performed under ambient conditions.
  • Fig. 9 shows a three-dimensional image taken from the cut side (thickness) of the composite film shown in Study 1. Image area is of 20x20 ⁇ . Loss of detail was observed when scanning this sample site, probably due to the increased interaction between the instrument tip and the sample surface, which resulted from higher water content inside the film sample than on its surface.
  • Fig. 10 shows the total cumulative octenidine release (%) at different time points from the Periodontal film shown in Study 1 in a combined saliva mix, as measured at room temperature, after incubation at 37°C, over 24 hours in total.
  • Two experiments were conducted, each with a saliva mix obtained from several donors.
  • certain parameters of the saliva e.g., viscosity
  • the saliva mixtures were not homogeneous and were characterized by air bubbles and/or mucos- like bodies. Due to the presence of those, it was difficult to take samples for measurements having accurate and uniform volume, and the samples taken at the last measurement points thus varied in volume and had smaller volume than that of the samples taken at the first measurement points.
  • Fig. 11 shows the changes (%) in the X, Y and Z dimensions of ⁇ 10kDa HA- and ⁇ 48kDa HA-based Periodontal films vs. PeriochipTM, in water, as measured at room temperature after 15-minute incubation period at 37°C.
  • the results relating to the ⁇ 10kDa HA-based Periodontal film and PeriochipTM were taken as an average from Figs. 2-4, and the results relating to the ⁇ 48kDa HA-based Periodontal film are the average of a duplicate experiment with error bars representing the standard deviation.
  • Fig. 12 shows the total cumulative octenidine release (%) from the ⁇ 48kDa hyaluronic acid (HA)-based Periodontal film vs. the ⁇ 10kDa HA-based Periodontal film, in a combined saliva mix, at different time points, as measured after incubation at 37°C over 24 hours in total.
  • the results relating to the ⁇ 10kDa HA-based Periodontal film are the average of those shown in Fig. 10, and the results relating to the ⁇ 48kDa HA-based Periodontal film are the average of a duplicate experiment.
  • a solid dosage form (referred to herein as an "oral delivary composition") comprising a gelatin matrix cross- linked via glutaraldehyde to a low molecular weight hyaluronan, e.g., hyaluronic acid having a molecular weight that is lower than 50000 Da, and a therapeutic agent, e.g., an antiseptic agent such as octenidine, upon contact with an aqueous fluid, adsorbs said fluid and swells, and consequently biodegrades and releases said therapeutic agent in a sustained release manner.
  • the low molecular weight hyaluronan chains actually contribute to a particular and unexpected swelling pattern of the solid dosage form, which seems to render said dosage form highly advantageous when used in treatment of periodontal disease.
  • Such solid dosage forms can be cut as an essentially two-dimensional film for implantation into a periodontal pocket, wherein upon insertion into a periodontal pocket, said film adsorbs fluids in the inflated pocket and swells, and consequently biodegrades and releases the therapeutic agent in a sustained release manner to thereby treat the periodontal disease; and upon degradation of the polymeric matrix, said low molecular weight hyaluronan contribute to the healing process of the inflamed tissue of the dental pocket.
  • peripheral pocket refers to an abnormal space between the cervical enamel of a tooth and the overlying unattached gingiva, resulting from a chronic inflammatory response associated with untreated gingivitis or periodontitis, which leads to destruction and fracture of the tissues and bone supporting said tooth.
  • the present invention thus provides an oral delivery composition, said composition being in a solid dosage form comprising: (i) a matrix comprising a water insoluble biodegradable or bioerodible pharmaceutically acceptable polymer, low molecular weight hyaluronic acid (also called hyaluronan or hyaluronate) or a salt thereof, and a cross- linking agent cross linking said polymer and said hyaluronic acid or salt thereof (i.e., crosslinked to said polymer and said hyaluronic acid or salt thereof); (ii) a plasticizer; and (iii) a therapeutic agent, wherein upon contact with a fluid, e.g., an aqueous fluid, said composition adsorbs said fluid and consequently swells, and then degrades and releases said therapeutic agent and said hyaluronic acid in a sustained release manner.
  • a fluid e.g., an aqueous fluid
  • the therapeutic agent comprised within the oral delivery composition of the invention is an antibacterial agent, also referred to herein as "antiseptic agent” or “disinfecting agent”.
  • antibacterial agent also referred to herein as "antiseptic agent” or "disinfecting agent”.
  • controlled release refers to the release of an active agent from a composition comprising it at predetermined intervals or gradually, in such a manner as to make the contained active agent available over an extended period of time, e.g., hours (e.g., up to 6, 12, 18, 24, 36, or 48 hours) or days.
  • the release profile of the therapeutic agent from the oral delivery composition of the present invention depends on various parameters such as the particular biodegradable or bioerodible pharmaceutically acceptable polymer used, and its amount in the composition; the ratio (by weight) between said polymer and the hyaluronan; the extent to which said polymer is cross-linked; and the biodegradation or bioerosion rate of said composition.
  • a certain amount of the therapeutic agent e.g., about 30%, 35%, 40%, 45%, 50%, 55% or 60%, by weight
  • a certain amount of the therapeutic agent might be released from the composition within the first several hours after swelling, e.g., within the first 4, 5, 6, 8, 10 or 12 hours after swelling, while the remainder of the therapeutic agent is slowly released afterwards due to the biodegradation or bioerosion of the composition, e.g., in a constant rate.
  • the water insoluble biodegradable or bioerodible pharmaceutically acceptable polymer comprised within the oral delivery composition of the invention is selected from polylactide (PLA), polyglycolide (PGA), poly(lactic-co-glycolic acid) (PLGA), chitosan oligosaccharide (Mahima et ah, 2015), dextran, starch, alginic acid, carrageenan, heparin, hydroxyethylcellulose, or a combination thereof.
  • the water insoluble biodegradable or bioerodible pharmaceutically acceptable polymer comprised within the oral delivery composition of the invention is a protein, more specifically a structural protein.
  • Partiuclar such proteins include, without being limited to, proteins derived from connective tissue such as collagen and gelatin; albumin proteins such as serum albumin, milk albumin, or soy albumin; enzymes such as papain, or chymotrypsin; serum proteins such as fibrinogen.
  • the water insoluble biodegradable pharmaceutically acceptable polymer comprised within the oral delivery composition of the invention is gelatin, preferably partially hydrolyzed gelatin.
  • the present invention does not require the use of proteins having a specific level of purity, and thus proteins of any grade of purity may be employed. It is, however, preferable to employ proteins having a high degree of purity, and especially a defined (i.e., specifiable) composition, since the use of such proteins increases the degree with which the release of the antibacterial agent may be controlled. Thus, it is more preferable to employ a degradation product of proteins such as gelatin (a degradation product of collagen), and degradation product of hyalarunan such as short chain (low molecular weight) hyaluronan or more precisely oligomeric hyaluronan.
  • gelatin a degradation product of collagen
  • hyalarunan such as short chain (low molecular weight) hyaluronan or more precisely oligomeric hyaluronan.
  • a preferred protein for use in the oral delivery composition of the invention is gelatin which has been partially hydrolyzed by enzymatic action to molecular weight of, e.g., 1000-12000 Daltons (Da).
  • Byco R proteins Chemical Colloids, Ltd.
  • Byco R C, A, and O having molecular weights in the range of about 8000 Da to about 30000 Da, have been found to be the preferred proteins for use in the polymeric matrix of the oral delivery composition.
  • the water insoluble biodegradable or bioerodible pharmaceutically acceptable polymer comprised within the oral delivery composition of the present invention is cross- linked to an extent that is sufficient to render said polymer insoluble but insufficient to prevent the release of said therapeutic agent from the composition, provided that it is capable of being degraded at the treatment site.
  • the biodegradable or bioerodible pharmaceutically acceptable polymer composing the matrix of the oral delivery composition is present at a concentration that is sufficient to provide said composition with structural stability, but insufficient to render said composition incapable of degradation, or incapable of permitting the release of said antibacterial agent.
  • the biodegradable or bioerodible pharmaceutically acceptable polymer is present in said composition in an amount of from about 10% to about 90%, preferably from about 20% to about 70%, or from about 30% to about 50%, more preferably from about 35% to about 45%, e.g., in an amount of about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, or about 45%.
  • the matrix composing the oral delivery composition of the present invention comprises a biodegradable or bioerodible pharmaceutically acceptable polymer as defined above, e.g., a protein such as gelatin, and hyaluronic acid or a salt thereof, wherein said polymer and hyaluronic acid or salt thereof are cross-linked via a cross-linking agent.
  • a biodegradable or bioerodible pharmaceutically acceptable polymer as defined above, e.g., a protein such as gelatin, and hyaluronic acid or a salt thereof, wherein said polymer and hyaluronic acid or salt thereof are cross-linked via a cross-linking agent.
  • the mixture of said polymer and hyaluronan or salt thereof in fact improves the bio-compatibility of the composition.
  • Hylauronic acid is an anionic, nonsulfated glycosaminoglycan (GAG) widely distributed throughout connective tissues of vertebrates, being the most abundant glycosaminoglycan of higher molecular weight in the extracellular matrix of soft periodontal tissues.
  • GAG glycosaminoglycan
  • Hyaluronan has important hygroscopic, rheological and viscoelastic properties that fluctuate with changes in temperature, pH, ionic environment, and binding partners. However, these properties are also highly dependent on chain length. Hyaluronan can reach over 10 7 Da in molecular mass, but also exists in multiple smaller forms, referred to as low molecular weight hyaluronan or oligomeric hyaluronan.
  • hyaluronan exerts varied bacteriostatic effects on all the bacterial strains tested, depending on its molecular weight and concentration, wherein high concentrations of medium molecular weight hyaluronan had the greatest bacteriostatic effect, particularly on the Actinobacillus actinomycetemcomitans, Prevotella oris, Staphylococcus aureus, and Propionibacterium acnes strains.
  • Hyaluronan has been found to be effective in treatment of inflammatory processes in medical areas such as orthopedics, dermatology and ophthalmology, and it has been further found to be anti-inflammatory and antibacterial in gingivitis and periodontitis therapy. Due to its tissue healing properties, it could be used as an adjunct to mechanical therapy in the treatment of periodontitis (Sukumar and Drizhal, 2007).
  • hyaluronan are immunosuppressive, antiangiogenic and anti-inflammatory, and were shown to protect against lymphocyte- mediated cytolysis (McBride and Bard, 1979), suppress septic responses to lipopolysaccharides, maintain immune tolerance, induce production of immunosuppressive macrophages, and reduce expression of inflammatory cytokines.
  • Such hyaloronan was further found to have antiaging and anticancer effects; and are known to cause cell cycle arrest, mediated by transmembrane association between cluster of differentiation 44 (CD44) and the intracellular protein merlin (Morrison et ah, 2001), and to protect against apoptosis by a mechanism mediated by nuclear factor kappa-B (NF- ⁇ ) (Jiang et ah, 2011).
  • CD44 cluster of differentiation 44
  • NF- ⁇ nuclear factor kappa-B
  • hyaluronan By contrast, short or low molecular weight hyaluronan are highly angiogenic, and immunostimulatory. Even the smallest fragment (the tetrasaccharide) has specific functions, with an ability to induce heat shock proteins and suppress apoptosis. The very smallest fragments apparently have the ability to ameliorate the intensity of the reactions induced by the small to intermediate- size fragments of hyaluronan. These small tetrameric to hexameric polysaccharides identify tissue injury through Toll-like receptors (TLRs) (Taylor et al, 2007). They also have the ability to inhibit the growth of tumor cells.
  • TLRs Toll-like receptors
  • Hyaluronan affects endothelial cell proliferation and monolayer integrity.
  • oligosaccharides were found to stimulate angiogenesis in vivo and endothelial cells proliferation in vitro.
  • the hyaluronic acid or salt thereof comprised within the oral delivery composition of the invention has a molecular weight that is lower than 50000 Da, e.g., from about 4000 Da to about 30,000 Da, 33000 Da, 36000 Da, 39000 Da, 42000 Da, 45000 Da or 48000 Da, preferably from about 4000 Da to about 48000 Da, from about 5000 Da to about 25000 Da, or from about 6000 Da to about 12500 Da, more preferably from about 6500 Da to about 8000 Da.
  • Hyaluronan having molecular weight of below 10000 Da is an important component of the extracellular matrix and has been used as a viscoelastic biomaterial for medical purposes, in cosmetics and as a drug delivery system.
  • the hyaluronic acid or salt thereof comprised with the oral delivery composition of the present invention is present in an amount of from about 0.001% to about 20%, preferably from about 0.01% to about 10%, or from about 0.1% to about 3%, more preferably from about 0.4% to about 2.5%, e.g., in an amount of 0.4-0.6%, 0.6-0.8%, 0.8-1.0%, 1.0-1.2%, 1.2-1.4%, 1.4-1.6%, 1.6-1.8%, 1.8-2.0%, 2.0-2.2%, or 2.2-2.5%.
  • hyaluronan salts include, without limiting, alkaline metal or alkaline earth metal salts of hyaluronan, e.g., hyaluronan sodium salt and hyaluronan potassium salt.
  • the cross-linking agent comprised within the matrix of the oral delivery composition of the present invention is an aldehyde such as glutaraldehyde or formaldehyde, aluminum, chromium, titanium zirconium, bisdiazobenzidine, phenol 2,4- disulfonyl chloride, l,5-difluoro-2,4-dinitrobenzene, urea, 3,6-bis(mercurimethyl)-dioxane urea, dimethyl adipimidate, or N,N'-ethylene-bis-(iodo-acetamide).
  • said cross-linking agent is an aldehyde, preferably glutaraldehyde.
  • cross-linking agent is present in the oral delivery composition in its crosslinked form, i.e., as cross-linking agent residues linked to the polymer molecules and to the hyaluronan, rather than in its free form.
  • the cross-linking agent comprised within the matrix of the oral delivery composition is present in an amount that is sufficient to render said polymer insoluble but insufficient to prevent the release of said therapeutic agent from the composition.
  • said crosslinked cross-linking agent is present in an amount of from about 0.1% to about 20%, preferably from about 0.5% to about 10%, or from about 1% to about 5%, more preferably from about 2% to about 4%, e.g., in an amount of about 2.0%, about 2.1%, about 2.3%, about 2.5%, about 2.7%, about 2.9%, about 3.1%, about 3.3%, about 3.5%, about 3.7%, about 3.9%, or about 4.0%.
  • Hyaluronic acid can be cross-linked via various functional groups, e.g., via the acetyl group (CH 3 C(0)-) after deacetylation, via the carboxylic acid group, or via one of the hydroxyl groups.
  • Hyaluronic acid can be cross-linked with glutaraldehyde via hemiacetal formation.
  • Hyaluronic acid was chemically cross-linked with glutaraldehyde, using uncross- linked hyaluronan films in acetone- water mixtures, to produce water- insoluble hyaluronan films having low water content (as low as 60 wt%) when brought into contact with phosphate-buffered saline of pH 7.4 at 37°C.
  • the plasticizer comprised within the oral delivery composition of the present invention is a phthalate ester (also termed phthalate), i.e., an ester of phthalic acid, a phosphate ester (also termed organophosphate), i.e., an ester of phosphoric acid, glycerin, or sorbitol.
  • a phthalate ester also termed phthalate
  • a phosphate ester also termed organophosphate
  • the plasticizer is glycerin.
  • the plasticizer comprised within the oral delivery composition of the present invention is present at a concentration of from about 0.01% to about 25%, preferably from about 0.1% to about 20%, from about 1% to about 20%, or from about 3% to about 15%, more preferably from about 5% to about 10%, e.g., at a concentration of about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%.
  • the oral delivery composition disclosed herein is aimed at releasing a therapeutic agent, e.g., an antiseptic agent, in a periodontal pocket in a sustained release manner, i.e., in a predetermined rate aimed at maintaining a constant drug concentration for a specific period of time, e.g., hours or days, with minimum side effects.
  • a therapeutic agent e.g., an antiseptic agent
  • therapeutic agent refers to any agent having a therapeutic effect that might be beneficial in treatment of periodontal disease, e.g., an antimicrobial agent; an antibacterial agent, also referred to herein as “antiseptic agent” or “disinfecting agent, more particularly a topical antiseptic; antifungal agent, also referred to herein as fungicide or fungistatic; an anti-inflammatory agent, e.g., a non-steroidal anti-inflammatory drug; and an anti-pain agent.
  • antifungal agents include, without being limited to, fluconazole, itraconazole, amphotericin B, voriconazole, nystatin, clotrimazole, econazole nitrate, miconazole, terbinafine, ketoconazole, enilconazole, boric acid, and miconazole.
  • non-steroidal anti-inflammatory drug refers to any non-steroidal anti-inflammatory drug/agent/analgesic/medicine, and relates to both cyclooxygenase (COX)-2 selective inhibitors such as celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib and lumiracoxib, as well as to COX-2 non-selective inhibitors such as etodolac, aspirin, naproxen, ibuprofen, indomethacin, piroxicam and nabumetone.
  • COX-2 selective inhibitors such as celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib and lumiracoxib
  • COX-2 non-selective inhibitors such as etodolac, aspirin, naproxen, ibuprofen, indomethacin, piroxicam and nabumetone.
  • anti-pain agents include, without being limited to, lidocaine, benzocaine, dibucaine, tetracaine, and proparacaine.
  • the antibacterial agent comprised within the oral delivery composition of the present invention is a topical antibacterial agent such as a quaternary ammonium compound (QAC) or a pharmaceutically acceptable salt thereof, e.g., benzalkonium chloride, or cetylpyridinium chloride; a guanidine compound or a pharmaceutically acceptable salt thereof, e.g., chlorhexidine, alexidine, or polyhexamethylene biguanide (PHMB); hexetidine, triclosan; liniment (Glossary of common dental product ingredients.
  • QAC quaternary ammonium compound
  • a pharmaceutically acceptable salt thereof e.g., benzalkonium chloride, or cetylpyridinium chloride
  • a guanidine compound or a pharmaceutically acceptable salt thereof e.g., chlorhexidine, alexidine, or polyhexamethylene biguanide (PHMB)
  • PHMB polyhexamethylene biguanide
  • the topical antiseptic agent comprised within the oral delivery composition of the present invention is the bispyridinamine octenidine (1, ⁇ ,4,4'- tetrahydro-N,N'-dioctyl- 1 , 1 '-decametylenedi-(4-pyridylideneamine)), an antimicrobial agent capable of inhibiting dental plaque (Bailey et ah, 1984), or a pharmaceutically acceptable salt thereof such as octenidine dihydrochloride (CAS -number 70775-75-6) that is exemplified herein.
  • Octenidine dihydrochloride is a cationic, surface active antimicrobial compound, which differs from QACs such as benzalkonium chloride, and guanidines such as chlorhexidine, by the lack of an amide- and ester structure in its molecule, which results in lower toxicity due to possible metabolites.
  • Octenidine can be sterilized by steam up to 130°C in aqueous solutions and stored at room temperature, making it suitable for long storage.
  • the stability of octenidine makes it a useful robust molecule that is insensitive to interactions with functional groups that might be present in the composition (e.g., during preparation and/or storage of the composition).
  • octenidine is stable and maintains its antimicrobial activity at an extremely broad pH range (1.6-12.2), which is particularly important in wound healing during which the wound pH changes.
  • the octenidine mode of action involves destabilization of the microorganism membrane, and this ensures that microorganisms exposed to said agent cannot develop drug resistance in a straightforward way, as the entire cellular structure, rather than a specific molecular target, is affected. Since octenidine is a hydrophobic compound, it requires an organic solvent such as ethanol or phenoxyethanol in order to be effectively administered.
  • organic solvents may cause substantial irritation, particularly when applied to inflamed tissue, and the drug should thus be introduced in a suitable manner, e.g., in a controlled release manner precisely at the site of microbial contamination (e.g., the periodontal pocket).
  • the topical antiseptic agent comprised within the oral delivery composition of the invention is octenidine, or a pharmaceutically acceptable salt thereof such as octenidine dihydrochloride.
  • octenidine or a pharmaceutically acceptable salt thereof such as octenidine dihydrochloride.
  • other pharmaceutically acceptable salts of octenidine include, without limiting, the dimesylate salt, the diesylate salt, the ditosylate salt, the disulfate salt, the disulfonate salt, the diphosphate salt, the dicarboxylate salt, the dimaleate salt, the difumarate salt, the ditartrate salt, the dibenzoate salt, the diacetate salt, the dihydrobromide salt, and the digluconate salt.
  • the antibacterial agent comprised within the oral delivery composition of the present invention is present at a concentration of from about 0.001% to about 55%, preferably from about 0.1% to about 45%, from about 1% to about 40%, or from about 10% to about 35%, more preferably from about 20% to about 30%, e.g., at a concentration of about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30%.
  • the oral delivery composition of the present invention upon contact with said fluid, adsorbs said fluid and consequently swells to up to about 115%, about 120%, or about 125%, in length; up to about 115%, about 120%, or 125% in width; and to about 120-150% in thickness, of its sizes before adsorbing said fluid, i.e., before swelling.
  • the oral delivery composition of the present invention has a dissolution profile in saliva, at 37°C, whereby about 30% to about 60%, or about 40% to about 50%, of said therapeutic agent is released over the first five hours.
  • the present invention provides an oral delivery composition as defined in any one of the embodiments above, wherein the biodegradable or bioerodible pharmaceutically acceptable polymer is gelatin, preferably partially hydrolyzed gelatin; said hyaluronic acid has a molecular weight that is lower than 50000 Da, e.g., from about 4000 Da to about 30,000 Da, 33000 Da, 36000 Da, 39000 Da, 42000 Da, 45000 Da or 48000 Da, from about 5000 Da to about 25000 Da, from about 6000 Da to about 12500 Da, or from about 6500 Da to about 8000 Da, optionally hydrolyzed or partially hydrolyzed; said cross-linking agent is glutaraldehyde; said plasticizer is glycerin; and said therapeutic agent is an antibacterial agent such as octenidine or a pharmaceutically acceptable salt thereof, e.g., octenidine dihydrochloride.
  • the biodegradable or bioerodible pharmaceutically acceptable polymer is gelatin, preferably partially hydroly
  • said polymer is present in said composition in an amount of from about 20% to about 70%, or from about 30% to about 50%;
  • said hyaluronic acid or salt thereof is present in said composition in an amount of from about 0.01% to about 10%, or from about 0.1% to about 3%;
  • said crosslinked glutaraldehyde is present in said composition in an amount of from about 1% to about 4%;
  • said plasticizer is present at a concentration of from about 3% to about 15%, or from about 5% to about 10%; and
  • said antibacterial agent is present at a concentration of from about 10% to about 40%, or from about 20% to about 30%.
  • Such oral delivery compositions may have a dissolution profile in saliva, at 37°C, whereby about 30% to about 60%, or about 40% to about 50%, of said antibacterial agent is released over the first five hours.
  • Oral delivery sustained release compositions as disclosed herein are formed through the solidification of a liquid solution, and may be prepared according to any procedure and utilizing any technique available, e.g., according to the process described in detail in the Examples section hereinafter.
  • Partiuclar such octenidine-containing compositions as exemplified herein can be prepared by (i) dissolving a hydrolyzed gelatin (e.g., Byco C) in water, while stirring, to obtain a solution of said hydrolyzed gelatin; (ii) adding a first amount of an alcoholic solution of a pharmaceutically acceptable octenidine salt, e.g., octenidine dihydrochloride, to said solution, and immediately thereafter adding glycerin to said solution, while stirring; (iii) adding aqueous glutaraldehyde to the solution obtained in step (ii), while stirring; (iv) adding a second amount of said alcoholic solution of pharmaceutically acceptable octenidine salt to the solution obtained
  • the oral delivery composition as defined in any one of the embodiments above may further comprise one or more additional therapeutic agents, e.g., one or more antiinflammatory agents in addition to the hyaluronan that has an anti-inflammatory activity.
  • additional therapeutic agents e.g., one or more antiinflammatory agents in addition to the hyaluronan that has an anti-inflammatory activity.
  • the oral delivery composition of the present invention is in fact a solid dosage form, e.g., in the form of a film.
  • the said solid dosage form is an essentially two- (or practically flat three-) dimensional solid implant adapted for implantation in a periodontal pocket.
  • Such a solid implant may have different shapes and may be, e.g., from about 3 to about 10 mm in length; and/or from about 1 to about 5 mm in width; and/or from about 0.01 to 0.5 mm in thickness.
  • the present invention thus relates to a method for treatment of periodontal disease in a subject in need thereof comprising the step of implantation of an oral delivery composition as defined in any one of the embodiments above (e.g., such a composition comprising an antibacterial agent), that is an essentially two-dimensional solid implant adapted for implantation in a periodontal pocket of said subject, to thereby release said therapeutic agent and said hyaluronic acid in said periodontal pocket in a sustained release manner.
  • an oral delivery composition as defined in any one of the embodiments above (e.g., such a composition comprising an antibacterial agent), that is an essentially two-dimensional solid implant adapted for implantation in a periodontal pocket of said subject, to thereby release said therapeutic agent and said hyaluronic acid in said periodontal pocket in a sustained release manner.
  • subject refers to any mammal, e.g., a human, non-human primate, horse, ferret, dog, cat, cow, and goat. In a preferred embodiment, the term “subject” denotes a human, i.e., an individual.
  • the solid dosage form implanted in a periodontal pocket of the subject treated comprises a matrix, a plasticizer, and a therapeutic agent, each as defined above, wherein the biodegradable or bioerodible pharmaceutically acceptable polymer composing said matrix is gelatin, preferably partially hydrolyzed gelatin; the hyaluronic acid or salt thereof composing said matrix has a molecular weight that is lower than 50000 Da, e.g., from about 4000 Da to about 30,000 Da, 33000 Da, 36000 Da, 39000 Da, 42000 Da, 45000 Da or 48000 Da, from about 5000 Da to about 25000 Da, from about 6000 Da to about 12500 Da, or from about 6500 Da to about 8000 Da, optionally hydrolyzed or partially hydrolyzed; the cross-linking agent cross-linking said polymer and said hyaluronic acid is glutaraldehyde; the plasticizer is glycerin; and the therapeutic agent is an antibacterial agent such as o
  • said polymer is present in said solid dosage form in an amount of from about 35% to about 45%;
  • said hyaluronic acid or salt thereof is present in said solid dosage form in an amount of from about 0.4% to about 2.5%;
  • said crosslinked glutaraldehyde is present in said solid dosage form in an amount of from about 1% to about 4%;
  • said plasticizer is present at a concentration of from about 6% to about 8%; and
  • said antibacterial agent is present at a concentration of from about 20% to about 30%.
  • the present invention relates to an oral delivery composition as defined in any one of the embodiments above (e.g., such a composition comprising an antibacterial agent), that is an essentially two-dimensional solid implant adapted for implantation in a periodontal pocket, for use in the treatment of periodntal disease.
  • an oral delivery composition as defined in any one of the embodiments above (e.g., such a composition comprising an antibacterial agent), that is an essentially two-dimensional solid implant adapted for implantation in a periodontal pocket, for use in the treatment of periodntal disease.
  • Gelatin powder Byco R C (Croda Colloids, Ltd) molecular weight 19-30 kDA was added to pure water and dissolved under mixing. Sixty parts from the octenidine 20% in absolute ethyl alcohol were mixed with glycerol, used as a plasticizer for the final product, and the homogenous solution was added into the gelatin solution. Crosslinking of the composition was performed using glutaraldehyde at about half the amount used to prepare the commercially available chip (PerioChip). Glutaraldehyde (10% solution in water) was divided into 5 portions which were added every 5 minutes with mixing after each addition. The left 40 parts of the octenidine alcoholic solution was then added into the gelatin crosslinking solution.
  • the last step of the product preparation was the addition of hyaluronic acid (Bloomage Freda Biopharm Co., Ltd., Oligo Hyaluronic Acid [HA-Oligo], ⁇ 10kDa, htt :// w w .bloomagefreda.coin/proen/id 16. html ; 10%), before full crosslinking is achieved, while mixing for 2 minutes.
  • the yellow solution thus obtained was poured into suitable drying flat (polystyrene) dishes or some other suitable material, at 360 mg/cm 2 , and the drying process was performed at ambient temperature.
  • the films formed were left to dry for few days up to one week, and the dry films obtained were peeled dry from the flat dishes and cut into chips having a suitable size.
  • Chips were packed in sealed blisters, so as to keep them under controlled humidity level, which keeps them hard enough, and not too flexible, for easy insertion under the gum line inside the gingival pocket (excess drying of the chips may result in brittle products that might be broken in use or hurt the gingival pocket tissue during insertion).
  • a Periodontal film was weighed in order to determine its initial weight, using electronic analytical balance (FA2004C series), and was then inserted into an Eppendorf containing 0.2 mL of purified water and placed in an oven preheated to 37°C in order to swell.
  • the Periodontal film was removed from the Eppendorf at pre-determined times of 15, 30 and 60 minutes. Excess of water was removed by absorbing it with a paper tissue and the chip was weighed. The swelling percentage was calculated using the formula I:
  • the X and Y dimensions of the chip were measured using a ruler in order to determine its initial dimensions, and the Z dimension (hight; referring to the height of the casted film) was measured using a calibrated caliper (Digital caliper, "Metric", IP67 model).
  • the chip was then inserted into an Eppendorf containing 0.2 mL of purified water and placed in an oven preheated to 37°C in order to swell.
  • the chip was removed from the Eppendorf at pre-determined times of 15, 30 and 60 minutes. Excess of water was removed by absorbing it with a paper tissue and the chip was measured again.
  • the change in each dimension was calculated in percentages using the formula II:
  • the Periodontal film was found to behave different than expected when contacted with water, and swelled absolutely different than the commercially available product.
  • the swelling of the Periodontal film is rather low in both the X-axis and Y-axis compared with that of Periochip; however, significantly higher than that of Periochip in the Z-axis.
  • the swelling of the Periodontal film in the X-axis reaches about 125% in 15 min, while the swelling of Periochip in that axis reaches more than 160% in 15 min and then falls down (Fig.
  • the Periodontal film bulk swelling is about half of the Periochip bulk swelling
  • the swelling of the Periodontal film is surprisingly significantly higher compared to that of the Periochip in the Z-axis, and much lower compared to the Periochip in the X and Y axes.
  • the chip dimensions for gingival pocket treatment have to be high in the X and Y axes, and low (thin) in the Z axis
  • these unexpected findings suggest that the Periodontal film will have better stability inside the gingival pocket, upon insertion, as it will have absolute change (length and width) that is much lower than that of the commercial chip.
  • the wet film matrix undergoes final crosslinking by the crosslinking agent(s) used, while at the same time, drying of the wet film is proceeding. It is postulated that due to the anisotropic nature of the drying process, the crosslinking becomes anisotropic as well. More specifically, while during early stages of the casting and drying phases, the film is in a fluid state with some freedom of the polymer chains constituting the composition matrix to arrange and interact with one another, as well as with the molecules of the crosslinking agent(s), the crosslinking process increases the viscosity of the film and consequently restricts the movement of the film constituents.
  • Hyaluronic acid is a highly hydrophilic biopolymer known as being capable of binding water (and thus as a natural humectant), and as being capable of substantially swelling in water. It seems that the swelling properties of hyaluronic acid are exhibited in this anisotropic composition prepared, by a high degree of swelling in the z direction rather than in the z and y directions.
  • the hyaluronic acid molecules added compete with the gelatin molecules on the water molecules available.
  • the gelatin hydrophilic motifs associate with one another rather than with water molecules, and the hydrophobic character of gelatin is thus more pronounced.
  • the crosslinking of the gelatin under these conditions results in less swelling in water as compared to that of gelatin crosslinked in the absence of hyaluronic acid.
  • the swelling in the x and y directions is relatively minor due to the enhanced hydrophobic nature of the gelatin core (or even absent, due to the fact that the chip is cut from a continuous flat crosslinked film); however, the swelling in the z direction (height) is remarkably higher due to the relatively high hyaluronan concentration in the outer hydrophilic coat.
  • the low molecular weight hyaluronan chain are gradually expelled out of the core formed during the crosslinking of gelatin, and these expelled hyaluronan molecules undergo gradual crosslinking with the glutaraldehyde. This way, the matrix formed is gradually enriched with hyaluronan going from inside the film towards its outer part.
  • Glutaraldehyde crosslinks both gelatin and hyaluronan chains, where crosslinking with the nucleophilic amino groups-containing gelatin chains is preferred over the slow crosslinking reaction with the hyaluronan side chains.
  • the minor swelling in the x-y direction of the product disclosed herein significantly reduces the probability that such a product will swell out of the dental pocket into which it is inserted. Swelling outside the dental pocket often results in higher probability of dislodgement of said product during use.
  • the minor swelling in the x-y direction of the product disclosed herein compred with that of the commercial product, is expected to significantly reduce the pain (toothache and gum ache) caused by the pressure developed inside the dental pocket as a result of the swelling in the x-y direction, which is one of the complains when using the commercial product and appears in more than 50% of the cases.
  • the composite film disclosed herein swells significantly less than the commercial product in the x-y direction and hence substantially reduces both the probability of dislodgment after insertion into the pocket and the pain associated with the expansion (swelling) of the product inside the pocket.
  • the fact that said composite film swells substantially more than the commercial product in the z axis is advantageous, as in this case, a better contact is secured between the inserted product and the inflamed walls of the gingival pocket, and the amount of drug released from the inserted composite film that may leak outside the treatment site is significantly reduced (Fig. 6).
  • the product disclosed herein can be positioned in an optimal structure hence fill the dental pocket and therefore prevent the re-infestation of the pocket by pathogenic bacteria.
  • hyaluronan chains expelled from the gelatin core are probably also crosslinked albeit at lower extent compared to the gelatin chains, and the relatively low-level of crosslinkage of those outer chains, mainly composed of hyaluronan, is responsible for the high level of swelling in the z axis schematically depicted in Fig. 5.
  • a Periodontal film was inserted into an Eppendorf containing 0.2 mL of saliva, obtained from several donors and mixed, and the Eppendorf was then placed in an oven preheated to 37°C to release octenidine into the saliva sample. 20 ⁇ ⁇ of saliva were removed at pre-determined times of 0.5, 1, 4, 8 and 24 hours, and diluted. Total octenidine release at each point was measured using a spectrophotometer (Biomate 3, Thermo Spectronic, USA), at a wavelength of 281 nm, in a cumulative manner, using a calibration curve that was determined on pure octenidine solution according to the formula III:
  • MoctRei. is the cumulative octenidine release ⁇ g
  • Moct. is the octenidine amount (dosage) per Periodontal film ( .g)
  • Mrotai octrei. is the total octenidine release (%).
  • the intitial burst release of the antiseptic agent was about 40-50% during the first 1-5 hours, reaching almost plateau and leaving about 50% of the octenidine content to be slowly released during several days, upon bio-degradation of the chip structural matrix (gelatin and hyaluronan) by proteinase and hyaluronase enzymes present in the tissue sourounding the treated gingival pocket (Fig. 10).
  • a ⁇ 48kDa HA-based Periodontal film was prepared following the exact procedure described in Study 1, using a particular batch of hyaluronic acid having a molecular weight of ⁇ 48kDa (Bloomage Freda Biopharm Co., Ltd., Hyaluronic Acid [HA-TLM], htip ://www . bloomagefreda.com/proen/id 1.6. html ) .
  • gelatin powder Byco R C (Croda Colloids, Ltd) molecular weight 19-30 kDa was added to pure water and dissolved under mixing.
  • octenidine 20% in absolute ethyl alcohol Sixty parts out of octenidine 20% in absolute ethyl alcohol were mixed with glycerol, used as a plasticizer for the final product, and the homogenous solution was added into the gelatin solution.
  • Crosslinking of the composition was performed using glutaraldehyde at about half the amount used to prepare the commercially available chip (PerioChipTM).
  • Glutaraldehyde (10% solution in water) was divided into 5 portions which were added every 5 minutes with mixing after each addition.
  • the left 40 parts of the octenidine alcoholic solution was then added into the gelatin crosslinking solution.
  • the last step of the product preparation was the addition of hyaluronic acid ⁇ 48kDa (10%), before full crosslinking is achieved, while mixing for 2 minutes.
  • the yellow solution thus obtained was poured into suitable drying flat (polystyrene) dishes or some other suitable material, at 360 mg/cm 2 , and the drying process was performed at 35°C.
  • the films formed were left to dry for 48 hours, and the dry films obtained were peeled dry from the flat dishes and cut into chips having a suitable size. Chips were packed in sealed blisters, so as to keep them under controlled humidity level.
  • the -48 kDa HA-based Periodontal film has shown a behavior very similar to that of the ⁇ 10kDa HA-based Periodontal film shown in Study 1, and definitely different than that of the commercially available PeriochipTM.
  • the swelling of the chip was anisotropic, more specifically rather low in both the X and Y axes compared with that of the PeriochipTM; however, remarkably higher than that of PeriochipTM in the Z-axis.
  • the swelling of the chip in each one of the X and Y axes reached about 120-140%, while the swelling in the Z axis was higher than that in the X and Y axes reaching about 150%.
  • the swelling of the commercially available PeriochipTM under the same conditions, in the X and Y axes is much higher than that in the Z axis that is practically negligible (Table 1; Fig. 11).
  • Periodontal measurements status was evaluated at the first control by a charting. This evaluation included (i) periodontal pockets depth (PPD) at 6 sites of each tooth which is more than 4 mm; (ii) recession (REC) level at each tooth in the buccal and lingual/palatal side; (iii) clinical attachment level (AL) of every tooth which enters the study for the distance between cement-enamel junction (CEJ) and the bottom of the pocket level (attachment loss was calculated according to the formula: PPD - (MG-marginal gingiva - CEJ to bottom of pocket); and (iv) tooth mobility and furcations.
  • PPD periodontal pockets depth
  • REC recession
  • AL clinical attachment level
  • Periodontal film devices were provided randomly into the deepest pockets at the teeth (test group), while contra laterally teeth were served as control (control group). Periodontal pockets that received the Periodontal film together with scaling and root planning in periodontal pockets at initial therapy (test group) were compared to the control group of pockets that received scaling and root planning alone.
  • Pirnazar P.; Wolinsky, L.; Nachmani, S.; Haake, S.; Pilloni, A.; Bernard, G.W.

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Abstract

La présente invention concerne une composition d'administration buccale, plus particulièrement une forme posologique solide, pour administrer un agent thérapeutique, par exemple, un agent antibactérien, à un tissu mou dans la cavité buccale telle qu'une poche parodontale de façon à traiter une maladie liée à la cavité buccale telle qu'une maladie parodontale; et un procédé d'utilisation.
PCT/IL2018/050217 2017-02-28 2018-02-27 Composition parodontale et procédé d'utilisation WO2018158763A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10786448B2 (en) 2018-01-18 2020-09-29 Christian Arnold Chewing gum composition comprising polyhexanide
EP3771337A1 (fr) * 2019-07-29 2021-02-03 The Procter & Gamble Company Composition antimicrobienne
EP3771338A1 (fr) * 2019-07-29 2021-02-03 The Procter & Gamble Company Composition antimicrobienne acide

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7125860B1 (en) * 2000-08-31 2006-10-24 Fidia Farmaceutici S.P.A. Cross-linked derivatives of hyaluronic acid
CN105168238A (zh) * 2015-08-13 2015-12-23 南京天纵易康生物科技股份有限公司 一种透明质酸温敏凝胶及其制备方法和应用
DE202016102375U1 (de) * 2015-05-05 2016-05-24 Contipro Pharma A.S. Dentales Mittel auf Basis von Hyaluronan und Octenidindihydrochlorid

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7125860B1 (en) * 2000-08-31 2006-10-24 Fidia Farmaceutici S.P.A. Cross-linked derivatives of hyaluronic acid
DE202016102375U1 (de) * 2015-05-05 2016-05-24 Contipro Pharma A.S. Dentales Mittel auf Basis von Hyaluronan und Octenidindihydrochlorid
CN105168238A (zh) * 2015-08-13 2015-12-23 南京天纵易康生物科技股份有限公司 一种透明质酸温敏凝胶及其制备方法和应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YADAV SK ET AL. ET AL.: "Advances in patents related to intrapocket technology for the management of periodontitis", RECENT PAT. DRUG DELIV. FORMUL., vol. 9, no. 2, 27 January 2015 (2015-01-27), pages 129 - 145, XP055540758 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10786448B2 (en) 2018-01-18 2020-09-29 Christian Arnold Chewing gum composition comprising polyhexanide
EP3771337A1 (fr) * 2019-07-29 2021-02-03 The Procter & Gamble Company Composition antimicrobienne
EP3771338A1 (fr) * 2019-07-29 2021-02-03 The Procter & Gamble Company Composition antimicrobienne acide
WO2021022287A1 (fr) * 2019-07-29 2021-02-04 The Procter & Gamble Company Composition antimicrobienne acide
WO2021022286A1 (fr) * 2019-07-29 2021-02-04 The Procter & Gamble Company Composition antimicrobienne
US11572532B2 (en) 2019-07-29 2023-02-07 The Procter & Gamble Company Antimicrobial composition

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